The invention relates to compounds of the formula I 
in which the symbols have the following meaning:
R1 is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or xe2x80x94CaH2axe2x80x94phenyl,
said xe2x80x94CaH2a-phenyl being unsubstituted or substituted by 1-3 substituents selected from F, Cl, Br, I, CF3, methyl, methoxy, hydroxyl and NR(8)R(9);
R(8) and R(9) independently of one another are H or (C1-C4)alkyl;
a is zero, 1or 2; or
R1 is xe2x80x94CbH2bxe2x80x94(C1-C9)heteroaryl,
which is unsubstituted or substituted by 1-3 substituents selected from F, Cl, Br, I, CF3, CH3, methoxy, hydroxy and NR(10)R(11);
R(10) and R(11) independently of one another are H or (C1-C4)alkyl;
b is zero, 1 or 2; or
R1 is xe2x80x94CdH2dxe2x80x94(C3-C7)cycloalkyl;
d is zero, 1 or 2;
R2 and R3 independently of one another are hydrogen, F, Cl, Br, I, CF3, xe2x80x94Cxe2x89xa1N, xe2x80x94NO2, CH2OR17, COxe2x80x94R6 or Oxe2x80x94R7;
R17 is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
R6 is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, OR30 or phenyl,
said phenyl being unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, hydroxyl and NR(31)R(32);
R(31) and R(32) independently of one another are H or (C1-C4)-alkyl;
R30 is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
R7 is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, or phenyl,
said phenyl being unsubstituted or substituted by 1-3 substituents selected from F, Cl, Br, I, CF3, methyl, methoxy, hydroxyl and NR(12)R(13);
R(12) and R(13) independently of one another are H or (C1-C4)-alkyl; or
R7 is (C1-C9)heteroaryl, which is unsubstituted or substituted by 1-3 substituents selected from F, Cl, Br, I, CF3, CH3, methoxy, hydroxyl and NR(14)R(15);
R(14) and R(15) independently of one another are H or (C1-C4)-alkyl; or
R2 and R3 independently of one another are alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or xe2x80x94CgH2g-phenyl,
said xe2x80x94CgH2g-phenyl being unsubstituted or substituted by 1-3 substituents selected from F, Cl, Br, I, CF3, methyl, methoxy, hydroxyl and NR(18)R(19);
R(18) and R(19) independently of one another are H or (C1-C4)alkyl;
g is zero, 1 or 2; or
R2 and R3 independently of one another are xe2x80x94CIH21-(C1-C9)heteroaryl,
which is unsubstituted or substituted by 1-3 substituents selected from F, Cl, Br, I, CF3, CH3, methoxy, hydroxyl and NR(20)R(21);
R(20) and R(21) independently of one another are H or (C1-C4)alkyl;
I is zero, 1 or 2; or
R2 and R3 independently of one another are SOnxe2x80x94R22;
n is zero, 1 or 2;
R22 is alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or xe2x80x94CsH2s-phenyl,
said xe2x80x94CsH2s-phenyl being unsubstituted or substituted by 1-3 substituents selected from F, Cl, Br, I, CF3, methyl, methoxy, hydroxyl and NR(34)R(35);
R(34) and R(35) independently of one another are H or (C1-C4)-alkyl;
s is zero, 1 or 2;
R4 and R5 independently of one another are hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, F, Cl, Br, I, CF3, xe2x80x94Cxe2x89xa1N, xe2x80x94NO2, SOpxe2x80x94R16, COxe2x80x94R23 or Oxe2x80x94R24;
p is zero, 1or 2;
R16 is alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl,
said phenyl being unsubstituted or substituted by 1-3 substituents selected from F, Cl, Br, I, CF3, methyl, methoxy, hydroxyl and NR(26)R(27);
R(26) and R(27) independently of one another are H or (C1-C4)-alkyl;
R23 is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or OR25;
R25 is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
R24 is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl,
said phenyl being unsubstituted or substituted by 1-3 substituents selected from F, Cl, Br, I, CF3, methyl, methoxy, hydroxyl and NR(28)R(29);
R(28) and R(29) independently of one another are H or (C1-C4)-alkyl;
and their physiologically tolerable salts.
Preferred compounds of the formula I are those in which:
R1 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or xe2x80x94CaH2a-phenyl,
said xe2x80x94CaH2a-phenyl being unsubstituted or substituted by 1-2 substituents selected from F, Cl, Br, CF3, methyl, methoxy, hydroxyl and NR(8)R(9);
R(8) and R(9) independently of one another are H or methyl;
a is zero or 1; or
R1 is (C1-C9)heteroaryl,
which is unsubstituted or substituted by one substituent selected from F, Cl, Br, CF3, CH3, methoxy, hydroxyl and NR(10)R(11);
R(10) and R(11) independently of one another are H or methyl; or
R1 is xe2x80x94CdH2d-(C3-C7)cycloalkyl;
d is zero or 1;
R2 and R3 independently of one another are hydrogen, F, Cl, Br, CF3, xe2x80x94Cxe2x89xa1N, xe2x80x94NO2, CH2OR17, COxe2x80x94R6 or Oxe2x80x94R7;
R17 is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
R6 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, OR30 or phenyl,
said phenyl being unsubstituted or substituted by 1-2 substituents selected from F, Cl, Br, CF3, methyl, methoxy, hydroxyl and NR(31)R(32);
R(31) and R(32) independently of one another are H or methyl;
R30 is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
R7 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
said phenyl being unsubstituted or substituted by 1-2 substituents selected from F, Cl, Br, CF3, methyl, methoxy, hydroxyl and NR(12)R(13);
R(12) and R(13) independently of one another are H or methyl; or
R7 is (C1-C9)heteroaryl,
which is unsubstituted or substituted by one substituent selected from F, Cl, Br, CF3, CH3, methoxy, hydroxyl and NR(14)R(15);
R(14) and R(15) independently of one another are H or methyl; or
R2 and R3 independently of one another are alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or xe2x80x94CgH2g-phenyl,
said xe2x80x94CgH2g-phenyl being unsubstituted or substituted by 1-2 substituents selected from F, Cl, Br, CF3, methyl, methoxy, hydroxyl and NR(18)R(19);
R(18) and R(19) independently of one another are H or methyl;
g is zero or 1; or
R2 and R3 independently of one another are (C1-C9)heteroaryl,
which is unsubstituted or substituted by one substituent selected from F, Cl, Br, CF3, CH3, methoxy, hydroxyl and NR(20)R(21);
R(20) and R(21) independently of one another are H or methyl; or
R2 and R3 independently of one another are SOnxe2x80x94R22,
n is zero, 1 or 2;
R22 is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or xe2x80x94CsH2s-phenyl,
said xe2x80x94CsH2s-phenyl being unsubstituted or substituted by 1-2 substituents selected from F, Cl, Br, CF3, methyl, methoxy, hydroxyl and NR(34)R(35);
R(34) and R(35) selected from H and methyl;
s is zero or 1;
R4 and R5 independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, CF3, xe2x80x94Cxe2x89xa1N, xe2x80x94NO2, SOpxe2x80x94R16, COxe2x80x94R23 or Oxe2x80x94R24;
p is zero, 1 or 2;
R16 is alkyl having 1, 2, 3 or 4 carbon atoms or phenyl, said phenyl being unsubstituted or substituted by 1-2 substituents selected from F, Cl, Br, CF3, methyl, methoxy, hydroxyl and NR(26)R(27);
R(26) and R(27) independently of one another are H or methyl;
R23 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or OR25;
R25 is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
R24 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
said phenyl being unsubstituted or substituted by 12-2 substituents selected from F, Cl, Br, CF3, methyl, methoxy, hydroxyl and NR(28)R(29);
R(28) and R(29) independently of one another are H or methyl;
and their physiologically tolerable salts.
Particularly preferred compounds of the formula I are those in which:
R1 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
said phenyl being unsubstituted or substituted by one substituent selected from F, Cl, Br, CF3, methyl, methoxy, hydroxyl and NR(8)R(9);
R(8) and R(9) independently of one another are H or methyl; or
R1 is (C1-C9)heteroaryl,
which is unsubstituted or substituted by one substituent selected from F, Cl, Br, CF3, CH3, methoxy, hydroxyl and NR(10)R(11);
R(10) and R(11) independently of one another are H or methyl; or
R1 is (C3-C7)cycloalkyl;
R2 and R3 independently of one another are hydrogen, F, Cl, Br, CF3, xe2x80x94Cxe2x89xa1N, xe2x80x94NO2, COxe2x80x94R6 or Oxe2x80x94R7;
R6 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, OR30 or phenyl,
said phenyl being unsubstituted or substituted by one substituent selected from F, Cl, Br, CF3, methyl, methoxy, hydroxyl and NR(31)R(32);
R(31) and R(32) independently of one another are H or methyl;
R30 is hydrogen or alkyl having 1, 2 or 3 carbon atoms
R7 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
said phenyl being unsubstituted or substituted by one substituent selected from F, Cl, Br, CF3, methyl, methoxy, hydroxyl and NR(12)R(13);
R(12) and R(13) independently of one another are H or methyl; or
R7 is (C1-C9)heteroaryl,
which is unsubstituted or substituted by one substituent selected from F, Cl, Br, CF3, CH3, methoxy, hydroxyl and NR(14)R(15); R4) and R(15) independently of one another are H or methyl; or
R2 and R3 independently of one another are alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or phenyl,
said phenyl being unsubstituted or substituted by one substituent selected from F, Cl, Br, CF3, methyl, methoxy, hydroxyl and NR(1 8)R(19);
R(18) and R(19) independently of one another are H or methyl; or
R2 and R3 independently of one another are (C1-C9)heteroaryl,
which is unsubstituted or substituted by one substituent selected from F, Cl, Br, CF3, CH3, methoxy, hydroxyl and NR(20)R(21);
R(20) and R(21) independently of one another are H or methyl; or
R2 and R3 independently of one another are SOnxe2x80x94R22;
n is zero or 2;
R22 is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or phenyl,
said phenyl being unsubstituted or substituted by 1-2 substituents selected from F, Cl, Br, CF3, methyl, methoxy, hydroxyl and NR(34)R(35);
R(34) and R(35) independently of one another are H or methyl;
R4 and R5 independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, CF3, xe2x80x94Cxe2x89xa1N, xe2x80x94NO2, SOpxe2x80x94R16, COxe2x80x94R23 or Oxe2x80x94R24;
p is zero or 2;
R23 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or OR25;
R25 is hydrogen or alkyl having 1, 2 or 3 carbon atoms;
R24 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
said phenyl being unsubstituted or substituted by one substituent selected from F, Cl, Br, CF3, methyl, methoxy, hydroxyl and NR(28)R(29);
R(28) and R(29) independently of one another are H or methyl;
R16 is alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
said phenyl being unsubstituted or substituted by one substituent selected from F, Cl, Br, CF3, methyl, methoxy, hydroxyl and NR(26)R(27);
R(26) and R(27) independently of one another are H or methyl;
and their physiologically tolerable salts.
Very particularly preferred compounds of the formula I are those in which:
R1 is alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
said phenyl being unsubstituted or substituted by one substituent selected from F, Cl, CF3, methyl and methoxy; or
R1 is (C1-C9)heteroaryl,
which is unsubstituted or substituted by one substituent selected from F, Cl, CF3, CH3 and methoxy; or
R1 is (C3-C7)cycloalkyl;
R2 and R3 independently of one another are hydrogen, F, Cl, CF3, xe2x80x94Cxe2x89xa1N, COxe2x80x94R6 or Oxe2x80x94R7;
R6 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, OR30 or phenyl,
said phenyl being unsubstituted or substituted by one substituent selected from F, Cl, CF3, methyl and methoxy;
R30 is hydrogen, methyl or ethyl;
R7 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
said phenyl being unsubstituted or substituted by one substituent selected from F, Cl, CF3, methyl and methoxy; or
R7 is (C1-C9)heteroaryl,
which is unsubstituted or substituted by one substituent selected from F, Cl, Br, CF3, CH3 and methoxy;
R2 and R3 independently of one another are alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or phenyl,
said phenyl being unsubstituted or substituted by one substituent selected from F, Cl, CF3, methyl and methoxy; or
R2 and R3 independently of one another are (C1-C9)heteroaryl,
which is unsubstituted or substituted by one substituent selected from F, Cl, CF3, CH3 and methoxy; or
R2 and R3 independently of one another are SOnxe2x80x94R22;
n is zero or 2;
R22 is alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
said phenyl being unsubstituted or substituted by 1-2 substituents selected from F, Cl, CF3, methyl and methoxy;
R4 and R5 independently of one another are hydrogen, methyl, F, Cl, CF3, xe2x80x94Cxe2x89xa1N, SO2xe2x80x94R16, COxe2x80x94R23 or Oxe2x80x94R24;
R16 is alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
said phenyl being unsubstituted or substituted by one substituent selected from F, Cl, CF3, methyl and methoxy;
R23 is hydrogen, methyl or OR25;
R25 is hydrogen, methyl or ethyl;
R24 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
said phenyl being unsubstituted or substituted by one substituent selected from F, Cl, CF3, methyl and methoxy;
and their physiologically tolerable salts.
In addition, preferred compounds of the formula I are those in which the radicals R1, R2, R3, R4 and R5 are as defined above and the biphenyl substituent is linked as in formula Ia, Ib, Ic, Id, Ie, If, Ig or Ih 
and their physiologically tolerable salts.
In addition, preferred compounds of the formula I are those in which the radicals R1, R2, R3, R4 and R5 are as defined above, where R4 and R5 are not simultaneously hydrogen.
Alkyl can be straight-chain or branched.
Cycloalkyl is also understood as meaning alkyl-substituted rings. (C1-C9)Heteroaryl is understood as meaning in particular radicals which are derived from phenyl or naphthyl, in which one or more CH groups are replaced by N and/or in which at least two adjacent CH groups (with formation of a five-membered aromatic ring) are replaced by S, NH or O. In addition, one or both atoms of the condensation site of bicyclic radicals (such as indolizinyl) can also be nitrogen atoms.
Heteroaryl is in particular furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl.
Stereocenters which may occur can have either the (R) or the (S) configuration.
Physiologically tolerable salts of compounds of the formula I are understood as being both their organic and inorganic salts, such as are described in Remington""s Pharmaceutical Sciences [17th Edition, page 1418 (1985)]. On account of the physical and chemical stability and the solubility, for acidic groups, inter alia, sodium, potassium, calcium and ammonium salts are preferred; for basic groups, inter alia, salts of hydrochloric acid, sulfuric acid, phosphoric acid or of carboxylic acids or sulfonic acids, such as, for example, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid and p-toluenesulfonic acid, are preferred.
The invention also relates to a process for the preparation of the compounds of the formula I, and their physiologically tolerable salts, which comprises reacting a compound of the formula II 
in which the radicals are as defined above and which are either known from J. Med. Chem. 1995, 38, 2357 or were prepared analogously, with cyanogen bromide. The reaction is carried out in a dipolar aprotic solvent which is stable to cyanogen bromide, for example acetonitrile, DMA, TMU or NMP, using a strong auxiliary base which is not very nucleophilic, such as, for example, K2CO3 or Cs2CO3. A suitable reaction temperature is a temperature from 0xc2x0 C. to the boiling point of the solvent used; a temperature from 60xc2x0 C., to 120xc2x0 C. is preferred.
The invention furthermore relates to the use of a compound of the formula 
in which:
a) X, Y and Z are,
identically or differently, N or CR(102)
b) R(1) is
1. (C1-C10)alkyl, 2. (C3-C10)alkenyl, 3. (C3-C10)alkynyl, 4. xe2x80x94OR(103), 5. (C3-C8)cycloalkyl, 6. (C4-C10)cycloalkylalkyl, 7. (C5-C10)-cyclo-alkylalkenyl, 8. (C5-C10)cycloalkylalkynyl, 9. xe2x80x94(CH2)mxe2x80x94Bxe2x80x94(CH2)nxe2x80x94R(104), 10. -benzyl, 11. a radical defined as under b) 1., 2., 3. or 9., which is monosubstituted by CO2R(103), 12. a radical as defined under b) 1., 2., 3. or 9., in which 1 to all hydrogen atoms are substituted by fluorine, or 13. the radical defined under b) 10., which is substituted on the phenyl by 1 or 2 identical or different radicals from halogen, (C1-C4)alkoxy and nitro,
c) R(102) is
1. hydrogen, 2. halogen, 3. nitro, 4. CvF2v+1, 5. penta-fluorophenyl, 6. cyano, 7. xe2x80x94Oxe2x80x94R(106), 8. phenyl, 9. phenyl(C1-C3)alkyl, 10. (C1-C10)alkyl, 11. (C3-C10)alkenyl, 12. phenyl(C2-C6)alkenyl, 13. 1-imidazolyl(CH2)mxe2x80x94, 14. 1,2,3-triazolyl(CH2)nxe2x80x94, 15. tetrazolyl(CH2)mxe2x80x94, 16. -(CH2)o-1xe2x80x94CHR(107)xe2x80x94OR(105), 17. xe2x80x94(CH2)oxe2x80x94Oxe2x80x94COxe2x80x94R(103), 18. xe2x80x94(CH2)oxe2x80x94Sxe2x80x94R(106), 19. xe2x80x94S(O)rxe2x80x94R(119), 20. xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)mxe2x80x94CHR(103)xe2x80x94OR(106), 21. xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)mxe2x80x94COxe2x80x94R(108), 22. xe2x80x94COxe2x80x94R(108), 23. xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)mxe2x80x94Oxe2x80x94COxe2x80x94R(107), 24. xe2x80x94(CH2)mxe2x80x94CH(CH3)xe2x80x94CO-R(108), 25. xe2x80x94(CH2)oxe2x80x94COxe2x80x94R(108), 26. xe2x80x94(CH2)oxe2x80x94Oxe2x80x94[Cxe2x95x90W]xe2x80x94NHxe2x80x94R(109), 27. xe2x80x94(CH2)oxe2x80x94NR(107)xe2x80x94[Cxe2x95x90W]xe2x80x94OR(109), 28. xe2x80x94(CH2)oxe2x80x94NR(107)xe2x80x94COxe2x80x94NHR(109), 29. xe2x80x94(CH2)oxe2x80x94NR(107)xe2x80x94SO2R(109), 30. xe2x80x94(CH2)oxe2x80x94NR(107)xe2x80x94[Cxe2x95x90W]xe2x80x94R(109), 31. xe2x80x94(CH2)nF, 32. xe2x80x94(CH2)nxe2x80x94Oxe2x80x94NO2, 33. xe2x80x94CH2xe2x80x94N3, 34. xe2x80x94(CH2)nxe2x80x94NO2, 35. xe2x80x94CHxe2x95x90Nxe2x80x94NR(105)R(107), 36. phthalimido(CH2)nxe2x80x94, 
43. xe2x80x94(CH2)nxe2x80x94SO2xe2x80x94NR(107)xe2x80x94CSxe2x80x94NR(106)R(109), 44. xe2x80x94(CH2)nxe2x80x94SO2xe2x80x94NR(107)xe2x80x94COxe2x80x94NR(106)R(109), 45. xe2x80x94(CH2)oxe2x80x94SO2R(109), 46. a radical as defined under c) 8. or 9., which is substituted on the phenyl by 1 or 2 identical or different radicals from halogen, hydroxyl, methoxy, trifluoromethyl, CO2R(103) and phenyl, 47. a radical as defined under c) 10., 11. or 19., in which one to all hydrogen atoms are substituted by fluorine, 48. the radical defined under c) 14., which is substituted by 1 or 2 identical or different radicals from methoxycarbonyl and (C1-C4)alkyl, 49. xe2x80x94(CH2)nxe2x80x94SO2xe2x80x94NR(107)xe2x80x94COxe2x80x94R(106), 50. xe2x80x94(CH2)nxe2x80x94SO2xe2x80x94NR(107)CSxe2x80x94R(106),
d) R(103) is
1. hydrogen, 2. (C1-C8)alkyl, 3. (C3-C8)cycloalkyl, 4. phenyl, 5. benzyl, 6. the radical defined under d) 2., in which 1 to all H atoms are substituted by fluorine;
e) R(104) is
1. hydrogen, 2. (C1-C6)alkyl, 3. (C3-C8)cycloalkyl, 4. (C2-C4)-alkenyl or 5. (C2-C4)alkynyl;
f) R(105) is
1. hydrogen, 2. (C1-C6)alkyl, 3. (C3-C8)cycloalkyl, 4. phenyl or 5. benzyl;
g) R(106) and R(109) are,
identically or differently, 1. hydrogen, 2. (C1-C6)alkyl which is unsubstituted or substituted by 1-3 substituents selected from (C1-C6)alkoxy which for its part can be substituted by 1-3 radicals from hydroxyl, (C1-C6)alkoxy, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, (C2-C10)alkenyl, hydroxyl, amino, mono-(C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)-alkoxycarbonylamino, (C6-C12)aryl(C1-C4)alkoxycarbonylamino, (C6-C10)aryl, (C6-C10)aryl(C1-C3)alkyl, (C1-C9)heteroaryl, carboxyl and (C1-C4)alkoxycarbonyl; 3. (C3-C8)cycloalkyl,
where the cycloalkyl moiety is unsubstituted or substituted by 1-3 substituents selected from (C1-C4)alkyl and (C2-C4)alkenyl; 4. (C3-C8)cycloalkyl(C1-C3)alkyl, 5. (C6-C12)aryl, preferably phenyl, 6. (C6-C10)aryl(C1-C4)alkyl, 7. (C1-C9)heteroaryl,
which can be partially or completely hydrogenated,
8. a radical defined as under g) 5., 6., 7., 9., 15., 16., 17., 19., 20. or 21., substituted by 1 or 2 identical or different radicals selected from halogen, hydroxyl, (C1-C4)alkyl, methoxy, nitro, cyano, CO2R(103), trifluoromethyl, NR(111)R(112) and 
9. (C1-C9)heteroaryl(C1-C3)alkyl,
where the heteroaryl moiety can be partially or completely hydrogenated,
10. (C1-C6)alkyl, in which 1 to all H atoms are substituted by fluorine, 11. (C2-C10)alkenyl, (C2-C10)-alkenoyl or (C2-C10)alkadienyl, 12. (C3-C8)-cycloalkenyl, 13. (C3-C8)cycloalkenyl(C1-C3)alkyl, 14. bi- or tricyclic (C4-C10)cycloalkenyl(C1-C4)alkyl,
which can also be substituted by 1-3 (C1-C4)-alkyl radicals;
15. (C6-10)aryl(C1-C4)alkyl, 16. (C6-C10)aryl(C3-C6)-alkenyl, 17. (C1-C9)heteroaryl(C3-C6)alkenyl, 18. (C3-C6)alkynyl, 19. (C6-C10)aryl(C3-C6)alkynyl, 20. (C1-C9)heteroaryl(C3-C6)alkynyl, 21. R(106) and R(109) together with the nitrogen atom carrying them are a heteroaryl,
which can also be partially or completely hydrogenated;
h) R(107) is
1. hydrogen, 2. (C1-C6)alkyl, 3. (C3-C8)cycloalkyl, 4. (C6-C12-aryl(C1-C6)alkyl, preferably benzyl, 5. phenyl or 6. (C1-C9)-heteroaryl;
i) R(108) is
1. hydrogen, 2. (C1-C6)alkyl, 3. (C3-C8)cycloalkyl, 4. phenyl-(CH2)qxe2x80x94, 5. OR(106), 6. NR(111)R(112) or 7. 
j) R(110) is
cyano, nitro or CO2R(107);
k) R(111) and R(112) are,
identically or differently, 1. hydrogen, 2. (C1-C4)alkyl, 3. phenyl, 4. benzyl, or 5. xcex1-methylbenzyl;
l) D is NR(113), O or CH2;
m) R(113) is
hydrogen, (C1-C4)alkyl or phenyl;
n) A is biphenylyl,
which is unsubstituted or substituted by 1-4, preferably 1 to 2, identical or different substituents R(114) or R(115);
o) R(114) is
1. halogen, 2. nitroso, 3. nitro, 4. amino, 5. cyano, 6. hydroxyl, 7. (C1-C6)alkyl, 8. (C1C4)alkanoyl, 9. (C1-C4)-alkanoyloxy, 10.CO2R(103), 11. methanesulfonylamino, 12. trifluoromethanesulfonylamino, 13. xe2x80x94COxe2x80x94NHxe2x80x94OR(109), 14. xe2x80x94SO2xe2x80x94NR(106)R(107), 15. xe2x80x94CH2xe2x80x94OR(107), 16. (C1-C9)-heteroaryl(CH2)qxe2x80x94, preferably 1-tetrazolyl, 17. (C7-C13)aroyl, 
xe2x80x83or
20. (C6-C12)aryl;
p) R(115) is
1. hydrogen, 2. (C1-C6)alkyl, 3. (C3-C8)cycloalkyl, 4. (C6-C12)-aryl, 5. (C7-C13)aroyl, 6. (C1-C4)alkoxy, 7. (C1-C4)-alkanoyloxy, 8. (C1-(C9)heteroaryl, 9. CO2R(103), 10. halogen, 11. cyano, 12. nitro, 13. NR(106)R(107), 14. hydroxyl, 15. xe2x80x94COxe2x80x94NHxe2x80x94CHR(105)xe2x80x94CO2R(103), 16. sulfo, 17. xe2x80x94SO3R(103), 18. xe2x80x94SO2xe2x80x94NR(107)xe2x80x94COxe2x80x94NR(106)R(109) or xe2x80x94SO2xe2x80x94NR(107)xe2x80x94CSxe2x80x94NR(106)R(109), 19. xe2x80x94NR(107)xe2x80x94COxe2x80x94NR(106)xe2x80x94SO2xe2x80x94CH2xe2x80x94R(105), 20. xe2x80x94C(CF3)2OH, 21. phosphonooxy, 22. xe2x80x94PO3H2, 23. xe2x80x94NHxe2x80x94PO(OH)2, 24. xe2x80x94S(O)rR(106), 25. xe2x80x94COxe2x80x94R(108), 26. xe2x80x94COxe2x80x94NR(106)R(109), 27. xe2x80x94CR(120)(OH)xe2x80x94PO(OH)2, 28. the radical defined under o) 20., 
32. 5-tetrazolylxe2x80x94NHxe2x80x94COxe2x80x94, 33. xe2x80x94COxe2x80x94NHxe2x80x94NHxe2x80x94SO2xe2x80x94CF3, 
40. xe2x80x94COxe2x80x94NHxe2x80x94SO2xe2x80x94R(119), 41. xe2x80x94SO2xe2x80x94NHxe2x80x94COxe2x80x94R(106) or 42. the radical defined under p) 4., substituted by 1 or 2 identical or different radicals selected from halogen, cyano, nitro, NR(106)R(107) and hydroxyl; 43. R(115) together with R(114) is xe2x80x94COxe2x80x94NHxe2x80x94SO2xe2x80x94, 44. xe2x80x94SO2xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94R(106), 45. xe2x80x94SO2xe2x80x94NHxe2x80x94SO2xe2x80x94NR(106)R(109), 46. xe2x80x94SO2xe2x80x94NHxe2x80x94SO2xe2x80x94R(106);
q) B is O, NR(107) or S;
r) W is O or S;
s) L is (C1-C3)alkanediyl;
t) R(116) is
CO2R(103) or CH2CO2R(103);
u) R(117) is
hydrogen, halogen, (C1-C4)alkyl or (C1-C4)alkoxy;
v) R(118) is
hydrogen, (C1-C4)alkyl or phenyl;
w) R(119) is
1. (C1-C6)alkyl, 2. (C3-C8)cycloalkyl, 3. phenyl, 4. benzyl or 5. the radical defined under w) 1., in which one to all H atoms are substituted by fluorine,
x) T is 1. a single bond, 2. xe2x80x94COxe2x80x94, 3. xe2x80x94CH2xe2x80x94, 4. xe2x80x94Oxe2x80x94, 5. xe2x80x94Sxe2x80x94,
6. xe2x80x94NR(121)xe2x80x94, 7. xe2x80x94COxe2x80x94NR(121), 8. xe2x80x94NR(121)xe2x80x94COxe2x80x94, 9. xe2x80x94Oxe2x80x94CH2xe2x80x94, 10. xe2x80x94CH2xe2x80x94Oxe2x80x94, 11. xe2x80x94Sxe2x80x94CH2xe2x80x94, 12. xe2x80x94CH2xe2x80x94S, 13. xe2x80x94NHxe2x80x94CR(120)R(122), 14. xe2x80x94NR(121)xe2x80x94SO2, 15. SO2xe2x80x94NR(121)xe2x80x94, 16. xe2x80x94CR(120)R(122)xe2x80x94NH, 17. xe2x80x94CHxe2x95x90CHxe2x80x94, 18. xe2x80x94CFxe2x95x90CFxe2x80x94, 19. xe2x80x94CHxe2x95x90CFxe2x80x94, 20. xe2x80x94CFxe2x95x90CHxe2x80x94, 21. xe2x80x94CH2xe2x80x94CH2xe2x80x94, 22. xe2x80x94CF2xe2x80x94CF2xe2x80x94, 23. xe2x80x94CH[OR(103)]xe2x80x94, 24. xe2x80x94CH(OCOR(105))xe2x80x94, 25.xe2x80x94C[Nxe2x95x90R(123)]xe2x80x94 or 26. xe2x80x94[R(124)O]xe2x80x94Cxe2x80x94[OR(125)]xe2x80x94
y) R(120) and R(122) are,
identically or differently, hydrogen, (C1-C5)alkyl, phenyl, allyl or benzyl;
z) R(121) is
hydrogen, (C1-C6)alkyl, benzyl or allyl;
axe2x80x2) R(123) is
1. NR(120)R(121), 2. ureido, 3. thioureido, 4. toluene-4-sulfonyl or 5. benzenesulfonylamino;
bxe2x80x2) R(124) and R(125) are,
identically or differently, (C1-C4)alkyl or together xe2x80x94(CH2)qxe2x80x94;
cxe2x80x2) Q is CH2, NH, O or S;
dxe2x80x2) m is 1, 2, 3, 4 or 5;
exe2x80x2) n is 1, 2, 3, 4 or 5;
fxe2x80x2) o is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
gxe2x80x2) q is zero or 1;
hxe2x80x2) r is zero, 1 or 2;
ixe2x80x2) v is 1, 2, 3, 4, 5 or 6;
and of their physiologically tolerable salts for the production of a medicament for the treatment or prophylaxis of illnesses caused by ischemic conditions, and also for the production of a medicament for the treatment of impaired respiratory drive.
In addition, the invention relates to the use of a compound of the formula I for the production of a medicament for the treatment or prophylaxis of illnesses caused by ischemic conditions;
and also the use of a compound of the formula I for the production of a medicament for the treatment or prophylaxis of cardiac infarct;
and also the use of a compound of the formula I for the production of a medicament for the treatment or prophylaxis of angina pectoris;
and also the use of a compound of the formula I for the production of a medicament for the treatment or prophylaxis of ischemic conditions of the heart:
and also the use of a compound of the formula I for the production of a medicament for the treatment or prophylaxis of ischemic conditions of the peripheral and central nervous system and of stroke;
and also the use of a compound of the formula I for the production of a medicament for the treatment or prophylaxis of ischemic conditions of peripheral organs and members;
and the use of a compound of the formula I for the production of a medicament for the treatment of states of shock;
and also the use of a compound of the formula I for the production of a medicament for use in surgical operations and organ transplantation;
and also the use of a compound of the formula I for the production of a medicament for the preservation and storage of transplants for surgical measures;
and also the use of a compound of the formula I for the production of a medicament for the treatment of illnesses in which cell proliferation is a primary or secondary cause; and thus their use for the production of an antiatherosclerotic or a composition against diabetic late complications, carcinomatous disorders, fibrotic disorders such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, or prostate hyperplasia;
and also the use of a compound of the formula I for the production of a medicament for the treatment of impaired respiratory drive;
and also a pharmaceutical which comprises an efficacious amount of a compound of the formula I.
Compounds similar to the compounds of the formula I according to the invention are disclosed in U.S. Pat. Nos. 5,482,957 and 5,604,251. However, they do not have the sulfonylcyanamide side chain always present according to the invention. Imidazole derivatives as angiotensin II antagonists are also described in WO9523792, WO9523791, U.S. Pat. No. 5.391.732, EP-A 648763. In addition, in U.S. Pat. No. 5,281,614, triazole derivatives and, in WO 9220662 and in J. Med. Chem. (1994), 37 (17), 2808-2824, triazolinone derivatives are described as angiotensin II receptor antagonists. The known compounds are angiotensin II receptor antagonists of the subtype AT1, which action is not present or is only present to a small extent in the compounds I according to the invention.
The compounds of the formula I according to the invention exhibit very good antiarrhythmic properties, such as are important, for example, for the treatment of illnesses which occur in the case of oxygen deficiency symptoms. Because of their pharmacological properties, the compounds of the formula I are outstandingly suitable as antiarrhythmic pharmaceuticals having a cardioprotective component for infarct prophylaxis and infarct treatment and also for the treatment of angina pectoris, where they also preventively inhibit or greatly decrease the pathophysiological processes in the formation of ischemically induced damage, in particular in the elicitation of ischemically induced cardiac arrhythmias.
Because of their protective actions against pathological hypoxic and ischemic situations, the compounds of the formula I according to the invention can be used, as a result of inhibition of the cellular Na+-dependent Clxe2x88x92/HCO3xe2x88x92 exchange mechanism or of the sodium /bicarbonate symporter, as a pharmaceutical for the treatment of all acute or chronic damage caused by ischemia or illnesses induced primarily or secondarily thereby. They protect organs which are acutely or chronically undersupplied with oxygen by reducing or preventing ischemically induced damage and are thus suitable as pharmaceuticals, for example in thrombosis, vasospasms, atherosclerosis or in surgical interventions (e.g. in kidney and liver organ transplantation, where the compounds can be used both for the protection of the organs in the donor before and during removal, for the protection of removed organs, for example during treatment with or storage thereof in physiological bath fluids, and in the transfer to the recipient""s body) or acute kidney failure. The compounds of the formula I are also valuable pharmaceuticals having a protective action when carrying out angioplastic surgical interventions, for example on the heart and also on peripheral vessels. Corresponding to their protective action against ischemically induced damage, the compounds are also suitable as pharmaceuticals for the treatment of ischemias of the nervous system, in particular of the central nervous system, where they are suitable, for example, for the treatment of stroke or of cerebral edema. Moreover, the compounds of the formula I according to the invention are also suitable for the treatment of forms of shock, such as, for example, of allergic, cardiogenic, hypovolemic and of bacterial shock.
Moreover, the compounds of the formula I according to the invention are distinguished by strong inhibitory action on the proliferation of cells, for example fibroblast cell proliferation and the proliferation of the vascular smooth muscle cells. Therefore the compounds of the formula I are suitable as valuable therapeutics for illnesses in which cell proliferation is a primary or secondary cause, and can therefore be used as antiatherosclerotics, agents against diabetic late complications, carcinomatous disorders, fibrotic disorders such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, organ hypertrophies and hyperplasias, in particular in prostate hyperplasia or prostate hypertrophy.
It was found that inhibitors of the Na+-dependent Clxe2x88x92/HCO3xe2x88x92 exchanger or of the sodium/bicarbonate symporter can stimulate the respiration by an increase in the chemosensitivity of the respiratory chemoreceptors. These chemoreceptors are responsible to a considerable extent for the maintenance of an ordered respiratory activity. They are activated by hypoxia, pH decrease and rise in CO2 (hypercapnia) in the body and lead to an adjustment of the respiratory minute volume. During sleep, the respiration is particularly susceptible to disturbance and is dependent to a great extent on the activity of the chemoreceptors.
Improvement in the respiratory drive by stimulation of the chemoreceptors with substances which inhibit Na+-dependent Clxe2x88x92/HCO3xe2x88x92 exchange leads to an improvement in the respiration in the following clinical conditions and illnesses: disturbed central respiratory drive (e.g. central sleep apnea, cot death, postoperative hypoxia), muscle-related respiratory disorders, respiratory disorders after long-term ventilation, respiratory disorders during adaptation in a high mountain region, obstructive and mixed forms of sleep apneas, acute and chronic lung diseases with hypoxia and hypercapnia.
Pharmaceuticals which contain a compound of the formula I can in this case be administered orally, parenterally, intravenously, rectally or by inhalation, the preferred manner of administration being dependent on the particular symptoms of the disorder. The compounds of the formula I can in this case be used on their own or together with pharmaceutical auxiliaries, namely both in veterinary and in human medicine.
Auxiliaries which are suitable for the desired pharmaceutical formulation are familar to the person skilled in the art on the basis of his expert knowledge. Beside solvents, gel-forming agents, suppository bases, tablet auxiliaries, and other vehicles, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers or colorants.
For an oral administration form, the active compounds are mixed with the additives suitable therefor, such as excipients, stabilizers or inert diluents, and brought by the customary methods into the suitable administration forms, such as tablets, coated tablets, hard capsules, aqueous, alcoholic or oily solutions. Inert excipients which can be used are, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. In this case preparation can be carried out both as dry and as moist granules. Suitable oily excipients or solvents are, for example, vegetable or animal oils, such as sunflower oil or cod liver oil.
For subcutaneous or intravenous administration, the active compounds, if desired with the substances customary therefor such as solubilizers, emulsifiers or further auxiliaries, are brought into solution, suspension or emulsion. Possible solvents are, for example: water, physiological saline solution or alcohols, e.g. ethanol, propanol, glycerol, and in addition also sugar solutions such as glucose or mannitol solutions, or alternatively a mixture of the various solvents mentioned.
Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active compound of the formula I in a pharmaceutically acceptable solvent, such as, in particular, ethanol or water, or a mixture of such solvents.
If required, the formulation can also contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers and also a propellant gas. Such a preparation contains the active compound customarily in a concentration from approximately 0.1 to 10, in particular from approximately 0.3 to 3, % by weight.
The dose of the active compound of the formula I to be administered and the frequency of administration depend on the potency and duration of action of the compounds used; additionally also on the nature and severity of the illness to be treated and on the sex, age, weight and individual responsiveness of the mammal to be treated.
On average, the daily dose of a compound of the formula I in the case of a patient weighing approximately 75 kg is at least 0.001 mg/kg, preferably 0.01 mg/kg, to at most 10 mg/kg, preferably 1 mg/kg, of body weight. In the case of acute episodes of the illness, for example immediately after suffering a cardiac infarct, higher and especially more frequent doses may also be necessary, e.g. up to 4 individual doses per day. In particular in the case of i.v. administration, for example in the case of an infarct patient in the intensive care unit, up to 200 mg per day may be necessary.
The compounds of the formula I can be employed as sole active compounds or in combination with other pharmacologically active compounds.
The compounds of the formula I and/or their physiologically tolerable salts can be employed to achieve an advantageous therapeutic action and, together with other pharmacologically active compounds, for the treatment or prophylaxis of the abovementioned symptoms, in particular for the treatment of cardiovascular disorders. Combination with inhibitors of the sodium/hydrogen exchanger (NHE) and/or with active substances from other classes of cardiovascular active compound is preferred.
The invention additionally relates very generally to the combination of a) NCBE inhibitors and/or their physiologically tolerable salts with NHE inhibitors and/or their physiologically tolerable salts; b) NCBE inhibitors and/or their physiologically tolerable salts with active substances from other classes of cardiovascular active compound and/or their physiologically tolerable salts and also c) of NCBE inhibitors and/or their physiologically tolerable salts with NHE inhibitors and/or their physiologically tolerable salts and with active substances from other classes of cardiovascular active compound and/or their physiologically tolerable salts. Preferred combinations are those in which NCBE inhibitors of the formula I and/or their physiologically tolerable salts are used.
The active compounds which are known and identified as NHE inhibitors are guanidine derivatives, preferably acylguanidine, inter alia such as are described in Edward J. Cragoe, Jr., xe2x80x9cDIURETICS, Chemistry, Pharmacology and Medicinexe2x80x9d, J. WILEY and Sons (1983), 303-341 or the NHE inhibitors mentioned in DE19737224.4. The disclosures of both of these documents are specifically incorporated by reference herein.
Suitable NHE inhibitors are, for example, also benzoylguanidines such as are described in U.S. Pat. Nos. 5,292,755, 5,337,3024, 5,364,868, 5,591,754, 5,516,805, 5,559,153, 5,571,842, 5,641,792, 5,631,293, EP-A 577024, EP-A 602522, EP-A 602523, EP-A 603650, EP-A 604852, EP-A 612723, EP-A 627413, EP-A 628543, EP-A 640593, EP-A 640588, EP-A702001, EP-A 713864, EP-A 723956, EP-A 754680, EP-A 765868, EP-A 774459, EP-A 794171, DE 19624178.2, DE 19713427.0; ortho-substituted benzoylguanidines, such as are described in EP-A 556673, EP-A 791577, EP-A 794172, DE 19624178.2; ortho-amino-substituted benzoylguanidines, such as are described in EP-A 690048; isoquinolines, such as are described in EP-A 590455; benzo-fused 5-membered ring heterocycles, such as are described in EP-A 639573; diacyl-substituted guanidines, such as are described in EP-A 640587; acylguanidines, such as are described in U.S. Pat. No. 5547953; phenyl-substituted alkyl- or alkenylcarboxylic acids bearing perfluoroalkyl groups, such as are described in U.S. Pat. No. 5567734, EP-A 688766; heteroaroylguanidines, such as are described in EP-A 676395; bicyclic heteroaroylguanidines, such as are described in EP-A 682017; indenoylguanidines, such as are described in EP-A 738712; benzyloxycarbonylguanidines, such as are described in EP-A 748795; phenyl-substituted alkenylcarboxylic acid guanidines bearing fluorophenyl groups, such as are described in EP-A 744397; substituted cinnamoylguanidines, such as are described in EP-A 755919; sulfonimidamides, such as are described in EP-A 771788; benzenedicarboxylic acid diguanidines, such as described in EP-A 774458, EP-A 774457; diarylcarboxylic acid diguanidines, such as are described in EP-A 787717; substituted thiophenylalkenylcarboxylic acid guanidines, such as are described in EP-A 790245; bis-ortho-substituted benzoylguanidines, such as are described in DE 19621319.3; substituted 1- or 2-naphthylguanidines, such as are described in DE 19621482.3 and DE 19621483.1; indanylideneacetylguanidines, such as are described in EP 96112275.1; phenyl-substituted alkenylcarboxylic acid guanidines such as are described in DE 19633966.9; aminopiperidylbenzoylguanidines, such as are described in EP 667341; heterocycloxybenzylguanidines, such as are described in EP-A 694537; ortho-substituted benzoylguanidines, such as are described in EP704431; ortho-substituted alkylbenzylguanidines, such as are described in EP-A 699660; ortho-substituted heterocyclylbenzoylguanidines, such as are described in EP-A 699666; ortho-substituted 5-methylsulfonylbenzoylguanidines, such as are described in EP-A 708088; ortho-substituted 5-alkylsulfonylbenzoylguanidines having 4-amino substituents, such as are described in EP-A 723963; ortho-substituted 5-alkylsulfonylbenzoylguanidines having 4-mercapto substituents, such as are described in EP-A 743301; 4-sulfonyl-or 4-sulfinylbenzylguanidines, such as are described in EP-A 758644; alkenylbenzoylguanidines, such as are described in EP-A 760365; benzoylguanidines having fused, cyclic sulfones, such as are described in DE 19548708; benzoyl-, polycyclic aroyl- and heteroaroylguanidines, such as are described in WO 9426709; 3-aryl/heteroarylbenzoylguanidines, such as are described in WO 9604241; 3-phenylbenzoylguanidines having a basic amide in the 5-position, such as are described in WO 9725310; 3-dihalothienyl- or 3-dihalophenylbenzoylguanidines having a basic substituent in the 5-position, such as are described in WO 9727183; 3-methylsulfonylbenzoylguanidines having certain amino substituents in the 4-position, such as are described in WO 9512584; amiloride derivatives, such as are described in WO 9512592; 3-methylsulfonyl-benzoylguanidines having certain amino substituents in the 4-position, such as are described in WO 9726253; indoloylguanidines, such as are described in EP-A 622356 and EP-A 708091; indoloylguanidines having a fused additional ring system, such as are described in EP 787728; methylguanidine derivatives, such as are described in WO 9504052; 1,4-benzoxazinoylguanidines, such as are described in EP-A 719766; 5-bromo-2-naphthoylguanidines, such as are described in JP 8225513; quinoline-4-carbonylguanidines having a phenyl radical in the 2-position, such as are described in EP-A 726254; cinnamoylguanidines, such as are described in JP 09059245; propenoylguanidines having a naphthalene substituent, such as are described in JP 9067332; propenoylguanidines having indole substituents, such as are described in JP 9067340; or heteroaryl-substituted acryloylguanidines, such as are described in WO 9711055, and their physiologically tolerable salts. The disclosures of all of these documents are specifically incorporated by reference herein.
Preferred NHE inhibitors are the compounds emphasized as preferred in the publications mentioned. Very particularly preferred compounds are cariporide (HOE642), HOE 694, EMD 96785, FR 168888, FR 183998, SM-20550, KBR-9032, and their physiologically tolerable salts. Most preferred is cariporide or its physiologically tolerable salt.
Examples of classes of active compounds having cardiovascular activity which can be combined advantageously with NCBE inhibitors therapeutically or can additionally be combined with combinations of NCBE inhibitors and NHE inhibitors are beta-receptor blockers, calcium antagonists, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, loop diuretics, thiazide diuretics, potassium-sparing diuretics, aldosterone antagonists, such as are employed, for example, in lowering of the blood pressure, and also cardiac glycosides or other agents increasing the contractile force in the treatment of cardiac insufficiency and of congestive heart failures, and also antiarrhythmics of the classes I-IV, nitrates, KATP openers, KATP blockers, inhibitors of the veratridine-activatable sodium channel, etc. For example, the following are thus suitable: the beta-blockers propanolol, atenolol, metoprolol; the calcium antagonists diltiazem hydrochloride, verapamil hydrochloride, nifedipine; the ACE inhibitors captopril, enalapril, ramipril; trandolapril, quinapril, spirapril, preferably ramipril or trandolapril; the angiotensin II receptor antagonists losartan, valsartan, telmisartan, eprosartan, tasosartan, candesartan, irbesartan; the loop diuretics furosemide, piretanide, torasemide; the thiazide diuretics hydrochlorothiazide, metolazone, indapamide; the potassium-sparing diuretics amiloride, triamterene, spironolactone; the cardiac glycosides digoxin, digitoxin, strophanthin; the antiarrhythmics amiodarone, sotalol, bretylium, flecainide; the nitrate glycerol trinitrate; the K+(ATP) openers cromakalim, lemakalim, nocorandil, pinacidil, minoxidil; the inhibitors of the veratridine-activatable Na+ channel.
An example of such a particularly advantageous combination component with NCBE inhibitors are blockers of the non-inactivating sodium channel (veratridine-activatable sodium channel). The combinations of an NCBE inhibitor with a blocker of the non-inactivating sodium channel (veratridine-activatable sodium channel) are suitable for infarct and reinfarct prophylaxis and infarct treatment and also for the treatment of angina pectoris and the inhibition of ischemically induced cardiac arrhythmias, tachycardia and the formation and maintenance of ventricular fibrillation, the combinations of an NCBE inhibitor with a blocker of the non-inactivating sodium channel also preventively inhibiting or greatly decreasing the pathophysiological processes in the formation of ischemically induced damage. Because of their enhanced protective actions against pathological hypoxic and ischemic situations, the combinations according to the invention of an NCBE inhibitor with a blocker of the non-inactivating sodium channel are used, as a result of enhanced inhibition of the Na+ influx into the cell, as pharmaceuticals for the treatment of all acute or chronic damage induced by ischemia or diseases induced primarily or secondarily thereby. This relates to their use as pharmaceuticals for surgical interventions, e.g. in organ transplantation, where the combinations of an NCBE inhibitor with a blocker of the non-inactivating sodium channel can be used both for the protection of the organs in the donor before and during removal, for the protection of removed organs, for example, also during storage thereof in physiological bath fluids, and also during transfer to the recipient""s body. The combinations of an NCBE inhibitor with a blocker of the non-inactivating sodium channel are likewise valuable, protectively acting pharmaceuticals when carrying out angioplastic surgical interventions, for example on the heart, and also on peripheral vessels. In accordance with their protective action against ischemically induced damage, the combinations of an NCBE inhibitor with a blocker of the non-inactivating sodium channel are also suitable as pharmaceuticals for the treatment of ischemias of the nervous system, in particular of the central nervous system, where they are suitable for the treatment of stroke or of cerebral edema. Moreover, the combinations according to the invention of an NCBE inhibitor with a blocker of the non-inactivating sodium channel are also suitable for the treatment of forms of shock, such as, for example, of allergic, cardiogenic, hypovolemic and bacterial shock.
Beside administration as a fixed combination, the invention also relates to the simultaneous, separate or sequential administration of NCBE inhibitors with NHE inhibitors and/or an additional active substance from another class of cardiovascular active compound for the treatment of the abovementioned diseases.
The invention additionally relates to a pharmaceutical preparation comprising a) an NCBE inhibitor and an NHE inhibitor and/or their physiologically tolerable salts; or b) an NCBE inhibitor and additionally an active substance from another class of cardiovascular active compound and/or their physiologically tolerable salts; or c) an NCBE inhibitor, an NHE inhibitor and additionally an active substance from another class of cardiovascular active compound, and/or their physiologically tolerable salts.
Preferred pharmaceutical preparations are those which contain a compound of the formula I and/or its physiologically tolerable salt as an NCBE inhibitor.
By combined administration, the effect of one combination component can be potentiated by the respective other component, i.e. the action and/or duration of action of a combination or preparation according to the invention is stronger or longer-lasting than the action and/or the duration of action of the respective individual components (synergistic effect). In the case of combined administration, this leads to a lowering of the dose of the respective combination component, compared with individual administration. The combinations and preparations according to the invention accordingly have the advantage that the amounts of active compound to be administered can be significantly reduced and undesirable side effects can be eliminated or greatly reduced.
The invention furthermore relates to a commercial pack, comprising as pharmaceutical active compound a) an NCBE inhibitor and an NHE inhibitor and/or their physiologically tolerable salts; or b) an NCBE inhibitor and additionally an active substance from another class of cardiovascular active compound and/or their physiologically tolerable salts; or c) an NCBE inhibitor, an NHE inhibitor and additionally an active substance from another class of cardiovascular active compound and/or their physiologically tolerable salts, in each case together with instructions for the use of these active compounds in combination for simultaneous, separate or sequential administration in the treatment or prophylaxis of the abovementioned syndromes, in particular for the treatment of cardiovascular disorders.
Preferred commercial packs are those which contain compounds of the formula I as NCBE inhibitors.
The pharmaceutical preparations according to the invention can be prepared, for example, by either intensively mixing the individual components as powders, or by dissolving the individual components in the suitable solvents such as, for example, a lower alcohol and then removing the solvent.
The weight ratio of NCBE inhibitor to the NHE inhibitor or the substance having cardiovascular activity in the combinations and preparations according to the invention is expediently 1:0.01 to 1:100, preferably 1:0.1 to 1:10.
The combination and preparations according to the invention contain a total of preferably 0.5-99.5% by weight, in particular 4-99% by weight, of these active compounds.
When used according to the invention in mammals, preferably in man, the doses of the various active compound components vary, for example, in the range from 0.001 to 100 mg/kg/day.
General Procedure for the Preparation of Sulfonylcyanamides from Sulfonamides
The sulfonamide starting material is dissolved in 10 ml/mmol of anhydrous acetonitrile, 3 mol equivalents of K2CO3 and one mol equivalent of a 5 N solution of BrCN in acetonitrile are added dropwise and the mixture is heated under reflux until conversion is complete (typical reaction time 1-6 hours). The reaction mixture is then chromatographed on silica gel without further working up.